Numerous natural products that are known to bind duplex DNA possess two key structural characteristics that allow tight binding interactions with their cellular target: a planar aromatic aglycone that intercalates the backbone of DNA, and one or more carbohydrate moieties that participate in non-covalent interactions with the major and/or minor grooves. C-Aryl glycosides, substances containing carbon-carbon bonds between an aromatic intercalator and one or more carbohydrate residues, may thus be viewed as promising candidates for the development of high affinity DNA-binding agents. Although it has been shown that aromatic intercalators containing attached glycosyl residues have a superior ability to bind DNA in comparison to intercalators lacking such residues, there exist in the literature no systematic studies quantitatively comparing the DNA binding affinity of intercalators containing one, two, or three appended glycosyl units. In the proposed research, we will prepare a series of mono-, bis-, and tris-C-aryl glucoside derivatives of the gilvocarcin M chromophore and evaluate their association constants for duplex DNA by fluoresence and ultraviolet spectrocopic techniques. Members of the gilvocarcin family of C-aryl glycoside natural products are ideal templates for undertaking such a study since they are known DNA-binding agents that possess high antitumor activity with low overall toxicity. The synthesis plan calls for the convergent assembly of protected carbohydrate, naphthalene, and o-iodobenzoic acid subunits, and will allow the preparation of four gilvocarcin C-glucoside derivatives in seven to nine steps. The key carbon-carbon bond-forming reactions between aromatic and carbohydrate moieties will involve the direct coupling of arylmetal (aryllithium or arylcuprate) reagents and sugar thiolactones, followed by stereoselective radical reduction of the intermediate hemithioketal. The proposed binding studies measuring the strength of interaction of our gilvocarcin derivatives with calf-thymus DNA, poly(dA/dT)7poly(dA/dT), and poly(dG/dC)7poly(dG/dC) will not only allow us to assess the degree to which the attachment of additional carbohydrates to the gilvocarcin chromophore alters DNA binding affinity, but also will allow us to establish a correlation between the site of carbohydrate attachment on the chromophore (corresponding to placement in the major and/or minor grooves) and DNA binding affinity; furthermore, the DNA sequence preferences of our derivatives will also be apparent from the data obtained. Since it has been hypothesized that the DNA sequence specificity of C-aryl glycoside natural products depends on the nature of the glycosidic substituents, these studies will pave the way for the eventual preparation of gilvocarcin derivatives bearing a variety of different carbohydrate moieties useful in establishing paradigms for the design of sequence-dependent DNA-binding ligands. Such molecules, if capable of selectively interacting with the promoters or coding regions of target genes, may ultimately be used for the regulation of gene transcription and as therapeutic agents for a wide range of disease states.